Although many antidepressant (AD) drugs of different classes are available, two major problems remain unsolved. The first is that there is almost always a lag period before they are effective, and the second that 20-30 percent of depressed patients do not respond adequately to AD medication. Several agents including the thyroid hormones triiodothyronine (T3) and thyroxine (T4) have been used to reduce the lag period of ADs and augment their effects in refractory patients. Work in our laboratory has focussed on basic mechanisms of such augmenting agents, which are only minimally understood, in order to strengthen the scientific basis for their clinical application. The focus of this proposal is on T3 and on the hypothesis that increased synaptic availability of serotonin (5-HT) and effects on 5-HT receptors of the 5-HT-1A and 5-HT-1B subtypes are pivotal to the augmentation of ADs by thyroid hormones. Our preliminary experiments have shown that 7-day administration of T3 to rats increases basal levels of 5-HT, as determined by in vivo microdialysis, in frontal cortex, and also potentiates the increase in 5-HT levels induced by chronic administration of clomipramine. In the present project we seek to establish the relationship between T3 and 5-HT levels by performing dose-dependence and time course studies, in the latter case both with T3 alone and with T3 given in conjunction with an AD. As well as measuring basal 5-HT levels, presynaptic 5-HT-1A receptor functioning will be determined by the effect of the 5-HT-1A receptor agonist 8-OH-DPAT to reduce 5-HT release as a result of somatodendritic autoreceptor activation. Terminal 5-HT-1B autoreceptor function will be assessed using the 5-HT-1B/1D receptor antagonist GR 127935. These measurements of presynaptic function will be performed in frontal cortex, hippocampus and hypothalamus since all these areas have been implicated in the pathology of depression. Post-synaptic 5-HT-1A receptor functioning in the hippocampus will be determined by the effect of 8-OH-DPAT on cyclic AMP levels. Post-synaptic 5-HT-1A receptor functioning in the hypothalamus will be measured by means of neuroendocrine challenge tests in which 8-OH-DPAT -induced release of plasma corticosterone, ACTH and oxytocin is measured. In addition, mRNA levels for the 5-HT-1A and 5-HT-1B receptors, and protein levels, will be determined in a variety of brain areas including pre- and post-synaptic sites. These experiments will permit a comprehensive assessment of the role of serotonergic mechanisms in AD augmentation by T3 and an empirical basis for its use in the treatment of depression.